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Ceruloplasmin Test: Low & High Levels + Increasing

Written by Wendy Phillips, PhD (Biology) | Reviewed by Selfhacked Science Team | Last updated:
Medically reviewed by
Jonathan Ritter, PharmD, PhD (Pharmacology) | Written by Wendy Phillips, PhD (Biology) | Reviewed by Selfhacked Science Team | Last updated:

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This post will tell you everything you need to know about ceruloplasmin, including the normal range, how to increase or decrease it and much more.

What Is Ceruloplasmin?

Ceruloplasmin (Cp) is an enzyme that is bound to and transports most of the copper in the blood. It also plays a role in iron metabolism [1, 2].

Ceruloplasmin blood tests are used in addition to copper tests to help diagnose Wilson’s disease and other disorders of copper metabolism [3, 4].

Ceruloplasmin also belongs to a group of proteins called “acute phase” proteins. This means that its levels will rise in inflammation and inflammatory diseases [5].

Ceruloplasmin has a complex network of interactions in the body, playing a role in many aspects of maintaining health. It is known to interact with at least 125 other proteins [6].

It acts as an antioxidant, with the ability to remove hydrogen peroxide and lipid peroxidases [7, 8, 9].

How & Where Ceruloplasmin is Produced

Ceruloplasmin has a water-soluble form that circulates in the blood and is primarily made in the liver. It is produced to a much lesser extent in other parts of the body, including the lung, spleen, bladder, gut tract, and lymph nodes [10].

Production of ceruloplasmin in the liver is stimulated by thyroid hormones [11].

In obese people, up to 22% of the circulating ceruloplasmin is secreted by fat cells [12].

The second form of ceruloplasmin is anchored to membranes. It is made in the brain, liver, lungs, and kidneys. This form is believed to play an important role in iron transport out of brain and liver cells [13, 14].

Human white blood cells produce both forms of ceruloplasmin, with peripheral blood lymphocytes having higher levels than all other lymphocyte subsets [15].

Ceruloplasmin Roles

Transports Copper

Ceruloplasmin must have copper attached for it to function.

The ceruloplasmin in blood transports copper throughout the body. The copper is then taken up by cells [16].

Between 70 and 95% of the copper in the blood is bound to ceruloplasmin [17, 18].

Free, unbound copper concentrations in the blood tend to increase when ceruloplasmin levels are low.

Deficiencies in copper can cause low levels of blood ceruloplasmin because the protein is degraded more quickly when it is not bound to copper [19].

Helps Iron Mobilization

Ceruloplasmin helps move iron out from storage in the tissue. In the brain and liver, ceruloplasmin promotes the movement of iron out of cells and loaded onto transferrin, the main iron carrier in blood [20].

Low levels of ceruloplasmin can cause iron accumulation in the brain, liver, and pancreas.

Deficiencies in dietary copper can lead to iron-related problems such as anemia, and it could possibly have to do with ceruloplasmin transporting iron, but mice bred without ceruloplasmin were not anemic. It seems that copper helps iron utilization independently of ceruloplasmin [21].

Testing Ceruloplasmin Levels

The most common test for ceruloplasmin is a blood test. The most common type of blood test does not differentiate between forms with and without activating copper [22].

Another type of tests that measures the activity of the ceruloplasmin in the blood is not widely available but is more informative in diagnosing some diseases. For example, activity levels were found to be better than blood levels alone for diagnosing Wilson’s Disease [23, 22].

Most routine medical testing of ceruloplasmin is from blood samples and less commonly from urine samples. The concentration or activity in specific tissues can be measured, but those measures are generally taken only for research purposes.

Some have proposed that ceruloplasmin blood tests are overused as their diagnostic predictive values are low [24].

Normal Adult References Range:

Every lab has different reference ranges. On average, the range is around:

  • 20-40 mg/dL (0.20 and 0.40 g/L) [3]
  • Men:18 – 36 mg/dL and Women: 18 – 53 mg/dL (Quest Values)

Abnormal Ceruloplasmin Levels May Signal Problems

Abnormal ceruloplasmin levels in the blood have been associated with a wide variety of health problems. Copper deficiencies and gene mutations can directly cause low ceruloplasmin levels and activity. However, for many abnormalities in ceruloplasmin levels, it is unclear whether they are a cause or a consequence of the associated health problems. Since ceruloplasmin has beneficial roles in the body, it’s more likely to be a consequence when it’s associated with a condition.

In some cases, ceruloplasmin levels in the blood are normal, but the activity (functionality) of the protein is compromised.

Low ceruloplasmin in the blood can increase levels of reactive oxygen species (RON), which can cause molecular damage and promote inflammation.

On the other hand, ceruloplasmin levels often increase during acute inflammatory conditions and autoimmune reactions.

Low Ceruloplasmin

Low ceruloplasmin levels can be caused by:

  • Copper deficiency [25], Stomach surgery (which can cause copper deficiency) [26]
  • Malnutrition (lack of protein or total calories) [27, 28]
  • Menkes disease (a genetic disorder that causes poor absorption of copper) [2930]
  • Aceruloplasminemia (a genetic disorder that results in a lack of ceruloplasmin production) [31]
  • Zinc supplements [32]
  • Wilson’s disease [22]
  • Liver scarring (fibrosis) [3334]
  • Nonalcoholic fatty liver disease (children) [35]
  • Jaundice [36]
  • Aceruloplasminemia [37]
  • Hereditary hemochromatosis [38]
  • Huppke-Brendyl syndrome (a rare disease caused by a mutation in the gene SLC33A1) [39]

Low ceruloplasmin may contribute to:

  • Iron accumulation/iron overload in tissues [4038]
  • Parkinson’s disease, due to an increased iron concentration in the brain [41, 42]
  • Alzheimer’s disease [43, 44]

Low ceruloplasmin has been found in:

  • Arteriosclerosis (without heart disease) [45]
  • Sepsis [46, 47]
  • Burn injury [48, 49]
  • Trauma, including burns (activity levels decreased in the first 24 hours) [50]

Low Ceruloplasmin is Caused by Liver Disease

Because most ceruloplasmin is made in the liver, liver disease may disrupt ceruloplasmin synthesis. Indeed, some types of liver disease are associated with decreased ceruloplasmin levels.

Wilson’s disease and hereditary hemochromatosis gene mutations cause metal accumulation in the liver and also are associated with low ceruloplasmin levels [51].

Children with fatty liver disease have lower levels of ceruloplasmin in blood [35].

Lower blood ceruloplasmin levels were associated with increased scarring of the liver in men with chronic hepatitis B [52].

Low Ceruloplasmin Occurs in Wilson’s Disease

While Wilson’s disease can present at any age, 97% of diagnoses occur before the age of 40 [53].

Both low blood ceruloplasmin levels together with brown discoloration in the outer cornea (Kayser-Fleischer rings) are diagnostic of Wilson’s disease [53].

Copper levels in a 24-hour urine sample also are effective in diagnosing Wilson’s Disease [54].

Symptoms of the disease include liver disease or failure, rupturing of red blood cells (hemolysis), and neurologic and psychiatric disorders [53].

Wilson’s disease is caused by a mutation, not in the ceruloplasmin gene but in the gene for another copper-binding protein: ATP7B. More than 370 different mutations in the gene have been associated with Wilson’s disease [53].

The ATP7B protein is involved in exporting copper. A defect in this gene can cause copper accumulation in the liver, resulting in liver disease or failure [55].

When copper export is impaired, it becomes unavailable for incorporation into ceruloplasmin. Without copper, ceruloplasmin loses functionality and is broken down more rapidly.

The disease occurs when a mutation in the gene is inherited from both the mother and father. The estimated prevalence of the disease ranges from 1 in 7,000 to 1 in 30,000 people. In England, 1 in 40 people might carry a recessive mutation in one of their two copies of the gene [56].

Without treatment, Wilson’s disease is fatal, but a variety of drug treatments that reduce copper levels in the body are effective in controlling the disease if diagnosed early. However, some copper chelating treatments have worsened brain symptoms in about 20% of patients [53].

Symptoms of Wilson’s disease include [57]:

  • Weakness
  • Fatigue
  • Anxiety
  • Stomach pain
  • High blood pressure
  • Rashes
  • Tremors
  • Poor coordination
  • Involuntary movement
  • Difficulty speaking
  • Poor impulse control
  • Poor memory
  • Depression
  • Anorexia
  • Dark rings around the eyes (Kayser-Fleischer rings)
  • Jaundice

Low Ceruloplasmin Occurs in Menkes Disease

Menkes disease is caused by a faulty ATP7A gene. It disrupts the absorption of copper and its incorporation into proteins that require copper to function, such as ceruloplasmin [58].

Because people have many proteins that require copper, the disease affects the body in many ways. Symptoms of the disease can occur early in infancy and include reduced body temperature, hypoglycemia, kinky hair, and eating difficulties. At 2 or 3 months of age, seizures may occur, and at 5 to 6 months the baby becomes weak and movements are abnormal [59].

While low levels of blood ceruloplasmin and copper occur with the disease, low levels of these two are common in healthy infants as well. Therefore, other factors must be taken into consideration for diagnosing infants [60].

The ATP7A gene is X-linked, and so Menkes disease occurs mostly in males. Females with a faulty version of the gene on one of their X chromosomes usually have a functioning copy on their other X chromosome. However, males who inherit an X-chromosome with a defective ATP7A gene do not have a second copy on their Y chromosome to compensate for it [30].

Low Ceruloplasmin from Gene Mutations (Aceruloplasminemia)

Although rare, at least 30 ceruloplasmin gene mutations have been identified in humans that cause a loss of function in the protein. Without ceruloplasmin, iron accumulates in the brain, causing neurons to die and resulting in the neurodegenerative disorder aceruloplasminemia [40].

Symptoms of the disease, such as dementia and loss of motor function, are usually first noticed by people in their 40s or 50s. Diabetes is also common in those with the disease [61, 40].

Aceruloplasminemia can be differentiated from similar neurodegenerative diseases by the presence of retinal degeneration, usually without vision loss [62].

Low Ceruloplasmin May Contribute to Neurodegenerative Disorders (Parkinson’s, Alzheimer’s)

Accumulation of iron in the brain and chronic inflammation are frequently associated with neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ALS (amyotrophic lateral sclerosis), and aceruloplasminemia [63].

Because ceruloplasmin helps stimulate the movement of iron out of brain cells and through the blood-brain barrier, lower ceruloplasmin levels could be responsible for increased iron accumulation [64, 65].

Treatment with an iron chelator reduced brain iron accumulation and delayed symptoms in mice without functional ceruloplasmin [66].

Iron accumulation in the brain and oxidative stress are frequently associated with Parkinson’s disease [67, 68].

Low ceruloplasmin activity has been observed in the blood and spinal fluid of some Parkinson’s patients. Also, low blood ceruloplasmin activity has been associated with earlier onset of Parkinson’s disease [42].

In contrast, people with Parkinson’s disease had higher ceruloplasmin levels in specific areas of the brain, possibly due to higher levels of oxidative stress in those areas [69].

Improvements in Parkinson’s disease symptoms by treatment with an iron chelator were greater in patients also having a ceruloplasmin gene mutation [70].

How to Increase Ceruloplasmin

Because low levels of ceruloplasmin are linked to low levels of copper, increasing copper intake may increase ceruloplasmin levels. If you’re taking zinc supplements, you may want to stop or decrease the dosage, since that can compete with copper.

Low levels of ceruloplasmin associated with iron deficiencies can be increased with iron supplements [71].

Conversely, iron chelation therapy in Parkinson’s patients increased blood ceruloplasmin levels and ceruloplasmin activity levels in the substantia nigra, with a greater effect in those with lower baseline ceruloplasmin levels [70].

Vitamin A supplementation may increase ceruloplasmin levels in rats deficient in the vitamin [72].

Ceruloplasmin levels increased in human cells when treated with vitamin D [73].

High Ceruloplasmin

High ceruloplasmin increases as a result of inflammation, rather than the protein having harmful effects itself. There are some exceptions such as cancer, since ceruloplasmin has potential to increase tumor growth. But it also could be a consequence of cancer in cases where inflammation is high.

High ceruloplasmin levels are found in:

  • Women (because of higher estrogen levels) [74, 22]
  • Women on hormone replacement therapy [75]
  • People with high copper levels [25]
  • People with iron deficiency [25]
  • Pregnancy [76]

The following drugs can also increase ceruloplasmin levels:

  • Estrogen [77]
  • Birth control pills [78]
  • Tamoxifen (Soltamox), a breast cancer treatment drug [79, 80]
  • Anticonvulsant drugs used to treat epilepsy, such as phenobarbital (Luminal), carbamazepine (Tegretol, Carbatrol, Epitol), phenytoin (Dilantin, Phenytek, Infatabs), and valproic acid (Convulex, Depakote, Epilim, Stavzor) [81]

Elevated levels are found in the following diseases/conditions:

Cases where ceruloplasmin is likely a consequence of the associated inflammation and is not causal:

  • Infections [8283]
  • All-cause mortality in heart failure patients [84]
  • Obesity [85, 12]
  • Diabetic kidney disease (nephropathy) [86]
  • Heart disease [87], Increased risk of heart attack, stroke, and death due to heart disease in chronic kidney disease patients [88], Risk of a major heart event [89, 75], severe unstable angina [90]
  • Metabolic syndrome [91, 92]
  • Diabetes (II) [93]…Increased ceruloplasmin levels in the urine are associated with diabetes [94]
  • Acute stroke [95], Ischemia of legs (increased ceruloplasmin activity) [96]
  • Psoriasis [97]
  • Rheumatoid arthritis [98, 99100]
  • Osteoporosis (due to low-grade inflammation) [5]
  • Psoriasis [101]
  • Asthma [102]
  • Epilepsy [103]
  • Lupus nephritis (urine) [104]
  • Preeclampsia (high blood pressure during pregnancy) [105]
  • Liver disease [83, 106]
  • Obsessive-compulsive disorder [107]
  • Alzheimer’s disease [108]
  • Schizophrenia [109]
  • Major depressive disorder [110]
  • Hyperthyroidism [83]
  • Primary biliary cirrhosis associated with inflammatory bowel disease [111]
  • Immune thrombocytopenic purpura (ITP) [112]
  • Children with Henoch-Schönlein purpura (HSP) [113]
  • Acute graft-versus-host disease [114]
  • Advanced disease and poor prognosis in bile duct cancer patients [115]

Cases where ceruloplasmin is higher and the role may be causal:

  • Cancer (lymphoma, prostate, breast, cervical, etc.) [116, 117, 118, 119, 120]
  • Tumors (breast, ovarian, kidney, colon, brain) [121]

Ceruloplasmin Increases During Inflammation and Infection

Increased levels of ceruloplasmin were observed in the nasal fluid of asthmatic subjects who experienced inflammation after being given aspirin [122].

Ceruloplasmin increased 5-fold during experimentally-induced inflammation and excessive oxygen levels (hyperoxia) in rat lungs [123].

The inflammatory cytokines interleukin-6 (IL-6) and interleukin-1 beta (IL-1β) can increase the production of ceruloplasmin and the release of iron from human cells. Combining these cytokines with copper-chelating substances further increases ceruloplasmin production [124, 125].

Monocytes increase ceruloplasmin production 20-fold when exposed to the protein interferon-gamma but not when exposed to other interferons [126].

Ceruloplasmin is higher in the urine of patients with urinary tract infections [127].

Ceruloplasmin levels, which have anti-infection properties, increase during infection by bacteria, viruses, and protozoans. However, it is still uncertain if its anti-infection properties are related to copper transport, iron limitation, or some other mechanism of action [128].

It has been proposed that its anti-bacterial properties play a role in protecting against inflammatory bowel disease and urinary tract infections [129, 130].

High Levels are Associated with Oxidative Stress

Higher levels of ceruloplasmin are found in the placenta of pregnant women with preeclampsia as compared to those with normal pregnancies. Another study found that increased ceruloplasmin levels in weeks 18 to 20 of pregnancy can predict future preeclampsia [131, 132].

Ceruloplasmin binds and potentially inhibits myeloperoxidase, a pro-oxidant enzyme, and lactoferrin during inflammation. It is speculated that these compounds prevent oxidative damage to tissues caused by iron [133, 134].

Prolonged exposure to bright light damage can cause oxidative stress. Ceruloplasmin levels increased in mice retina following exposure from extended periods of bright light [135].

High Ceruloplasmin is Associated with Heart Disease

Heart disease is associated with inflammation, oxidative stress, and malfunction of nitric oxide processes, which are all associated with high levels of ceruloplasmin [136, 137].

High ceruloplasmin levels predicted an increased risk of heart disease in both men and women. High levels of ceruloplasmin also are associated with an increased risk of dying due to heart failure [75, 138].

High levels have also been associated with the risk of abnormal heart rhythm (atrial fibrillation) [139].

Ceruloplasmin acts both as an antioxidant and oxidant, depending on conditions. It can oxidize low-density lipoprotein, a molecule with a suspected role in atherosclerosis (hardening of the arteries) [140, 141].

High Ceruloplasmin May Be One of the Many Causal Factors for Cancer

Ceruloplasmin, or perhaps the copper it carries, can stimulate blood vessel formation [142]. This means it may play some contributory role in cancers.

As tumors grow, new blood vessels are needed to supply nutrients to the growing cells, and copper-carrying ceruloplasmin is involved in that process [143].

Treatment with copper-chelating agents reduced tumor blood vessel density and growth in mice [144].

Increases in blood ceruloplasmin levels are associated with a wide range of cancers, including:

  • Chronic lymphocytic leukemia [145]
  • Kidney [146]
  • Prostate [147]
  • Colon [147]
  • Brain [148]
  • Lymphoma [36]
  • Obesity-associated cancer cells [12]
  • Oral cancers [149]
  • Activity increased in breast, lung, gut, and gynecological [150]
  • Bile duct [151]

Alzheimer’s Disease

Alzheimer’s disease is associated with increased levels of ceruloplasmin and serum copper. Copper increases ceruloplasmin, but the higher ceruloplasmin isn’t explained completely by higher copper levels [152, 93, 153].

The ratios of ceruloplasmin to transferrin and copper levels are predictive of Alzheimer’s disease progression [154, 155].

Increased levels of free copper in the blood of Alzheimer’s patients are associated with a greater decline in cognitive function [156].

Increased levels of ceruloplasmin have also been observed in the brains of people with Alzheimer’s disease. It is unclear whether the change in ceruloplasmin levels in the brain is associated with problems related to iron, copper, or oxidative stress. The change may be due to the breakdown of regulating normal copper levels [157, 69].

In other studies, lower ceruloplasmin is associated with Alzheimer’s disease [43, 44].

It’s possible that in some cases, higher ceruloplasmin is a consequence of the inflammation that occurs in Alzheimer’s disease, while in other cases low ceruloplasmin contributes to the disease by causing copper overload.

Another copper-containing protein is thought to play a role in Alzheimer’s disease: amyloid precursor protein (APP). Like ceruloplasmin, APP helps export iron. However, unlike ceruloplasmin which removes iron from neurons, APP removes iron from the cells that support neurons (astrocytes) [158].

How to Decrease Ceruloplasmin

A combination of caloric restriction and exercise reduced ceruloplasmin levels after 6 months in non-smoking, healthy, overweight adults (ages 25 to 50 years) [159].

When rat brains were injected with hepcidin, which is another ferroxidase, ceruloplasmin levels in the brain decreased [160].

For diseases that are associated with higher ceruloplasmin levels, treatment of the disease can sometimes reduce ceruloplasmin levels. For example, ceruloplasmin levels decreased in patients with lupus after 3 months of treatment with a drug that reduces prolactin [161].

In diabetic rats with high ceruloplasmin levels, treatment with Tinospora cordifolia, a plant native to India, reduced ceruloplasmin levels [162].

After 3 months of treatment with melatonin, ceruloplasmin levels decreased in patients with multiple sclerosis [163].

If you also have excess copper levels (copper toxicity), you should:

  • Avoid copper-rich foods, such as liver (especially beef), seafood (shrimp), potatoes, beans, avocados, mushrooms, and soy products [164]
  • Eat low-copper foods that are high in zinc, such as eggs, oysters, and many fruits and vegetables [164]
  • Eat foods high in fiber or carbohydrates, which may decrease copper absorption [165, 166]
  • Stop using copper cookware because it can transfer some copper to your food [164]
  • Check the water you are drinking, and filter it if necessary. A lot of dietary copper can come from the water we drink [167]

Supplements that can help reduce copper:

  • Zinc [32]
  • Molybdenum [168]

Ceruloplasmin and Vitamin C

Supplementation with high levels of vitamin C (605 mg/day) did not decrease ceruloplasmin levels in the blood but did decrease ceruloplasmin activity [169].

Supplementation with high levels of vitamin C (2 grams/day) increased ceruloplasmin levels in guinea pigs but not human males [170].

High vitamin C levels in the blood are often correlated with low ceruloplasmin levels [171].

Irregular Ceruloplasmin Levels?

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